Atherosclerosis is a progressive, chronic inflammatory disease of large arteries in which lesions preferentially occur at vessel sites exposed to rapid changes in blood flow. Three common features of atherosclerotic plaques: localization in areas of disturbed flow, the presence of tissue factor and platelet-endothelial cell adhesion molecule 1(PECAM-1) dependence will be the central focus of this competitive renewal. Our hypotheses are that EC response to atherogenic stimuli will depend on its location in the circulation because of regional patterns of blood flow and wall strain. The underlying hemodynamic environment that EC are exposed to will sensitize EC to chemical stimuli. Different flow patterns and magnitudes activate different mechanosensors differently, leading to activation of canonical signal cascades with specific temporal and magnitude characteristics, resulting in defined EC phenotype. This EC phenotype manifests in differential gene expression which determine whether it is atheroprotective or atheroprone. Temporal or spatial gradients in these hemodynamic forces are more potent stimuli for EC than the actual magnitude of the force. PECAM-1 is an important EC mechanosensor that promotes atherosclerosis under disturbed flow conditions but not under laminar flow conditions. TF is involved in atherogenesis and is regulated by mechanical and chemical stimuli and PECAM-1 In my previous Merit grants, we investigated how EC sense and respond to mechanical and chemical signals. Our current thrust has been to try to understand how these cues interact and synergize around cell sensors, such as PECAM-1 to regulate dynamic vascular cell signaling and cell phenotype that promote atherogenesis. The objective of the current proposal is to investigate the effects of different patterns of steady and disturbed mechanical forces on human EC expression of TF, and to assess the activation of the relevant signal pathways and their regulation by potential mechanosensors such as, PECAM-1. The ability to sense and transduce local hemodynamic forces is unique to ECs, suggesting that the underlying mechanisms represent important therapeutic targets. In vivo correlation by investigating regions of uniform and disturbed flow in single and double knock out mice combining the ApoE -/- mouse model of atherosclerosis with the PECAM-1 -/- mouse will provide important translational correlation with our in vitro studies and advance our understanding of the role of mechanical forces in atherogenesis. PUBLIC HEALTH RELEVANCE: In caring for the expanding and more aged veteran population, the number of surgical and endovascular procedures for the treatment of the symptoms of atherosclerosis, performed in VA Medical Facilities has been rising in the last decade. It is crucial to understand the effects of hemodynamic forces on blood vessels since an ability to modulate these pathways may lead to prevention or reduction in atherosclerosis. Should this research be fruitful and accomplish its goal, it will have a direct impact on care of VA patients, extending their life, and quality of life. The cost savings of preventing or reducing atherosclerosis would save the VA, and the whole country, many millions of dollars each year. A better understanding of the mechanical effects of hemodynamic forces of the circulation on the vascular wall, which may contribute to these processes, and therefore, the discovery of sites for potential drug interference would represent a major advance in prolonging the lives of our VA patients.